Our overall goal is a compreiiensive molecular genetic and functional analysis of two of the most common soft tissue sarcomas, myxofibrosarcoma (MYXF) and pleomorphic malignant fibrous histiocytoma (PMFH), so as to elucidate the mutational programs and pathways involved in sarcomagenesis and to identify novel therapeutic targets. Tissue samples and cell lines of MYXF and PMFH will be subjected to a multiplatform genome-wide characterization of expression of protein-coding genes and microRNAs, DNA copy number changes, activating mutations, and gene rearrangements. These data will be used to identify both genetically distinct subtypes of MYXF and PMFH and molecular signatures associated with tumor morphology, grade, recurrence, and survival. To identify potential therapeutic targets, we will screen the genes and microRNAs in these signatures for involvement in proliferation, differentiation, and survival of MYXF and PMFH cell lines. Potential targets will be validated by functional assays in additional cell lines and in xenografts. To achieve these goals, we have assembled a multidisciplinary group of investigators armed with 2 unique resources: a database of prospectively collected clinical-pathologic and outcomes data on over 8300 patients treated for soft tissue sarcoma at MSKCC, and a linl<ed tissue banl< with over 5500 sarcoma samples and 68 primary sarcoma cell lines. The highly interactive and synergistic collaboration between MSKCC and Rocl<efeller will ensure maximum productivity in molecular target identification. The comprehensive information generated will facilitate the development of new subtype-specific targeted therapies for MYXF and PMFH.